Highly water-soluble salts of a short acting phenylalkylamine calcium channel blocker and uses thereof

ABSTRACT

The present invention includes surprisingly water-soluble salts of a phenylalkylamine compound that are potent antagonists of L-type calcium channels. Aqueous solutions including salts of the instant invention are formulated for nasal administration and provide a novel therapeutic platform for the treatment of stable angina, migraine, and cardiac arrhythmia, such as paroxysmal supraventricular tachycardia.

BACKGROUND OF THE INVENTION

The invention relates to salts including a phenylalkylamine compoundthat exhibit surprisingly high solubility in aqueous solution. The saltsof the instant invention are validated antagonists of L-type calciumchannels and provide a new therapeutic platform for the treatment ofcardiac arrhythmias, such as paroxysmal supraventricular tachycardia,stable angina, and migraines.

Cardiac Arrhythmia

Cardiac arrhythmia, or abnormal heart rhythm, is caused by abnormalexcitation and conduction to the heart. A normal heartbeat is regulatedby the sinoatrial (SA) node, a collection of cells embedded within theright atrium proximal to the superior vena cava. Under healthyphysiological conditions, the SA node spontaneously initiates actionpotentials at regular intervals and propagates these electrochemicalsignals from the right atrium to the left atrium. Each coordinated pulseinduces an influx of calcium ions (Ca²⁺) into the cardiomyocyte fibersof the SA node through voltage-gated calcium channels, which ultimatelyenables the cardiac muscle tissue to contract and expel blood from theatria into the ventricles. This signal is subsequently propagated to theatrioventricular (AV) node, which propagates the action potential to theright and left ventricles. This signal triggers an influx ofextracellular calcium, which in turn facilitates contraction ofventricular cardiomyocytes and the expulsion of blood from the heart andinto circulation.

The precise coordination of these events is vital to maintaining aregular heartbeat, and the aberrant activity of this electrochemicalconduction system gives rise to arrhythmia. A recurrent arrhythmia withan abrupt onset and termination is designated as paroxysmal. Symptoms ofparoxysmal supraventricular tachycardia (PSVT) include episodes ofregular and paroxysmal palpitations with sudden onset and termination(Blomstrom-Lundqvist et al., J. Am. Coll. Cardiol., 2003, 42:1493-531).The signaling mechanisms that underlie PSVT include the initiation andpropagation of action potentials along accessory nodes that causeabnormal cardiomyocyte contractions that interfere with the coordinatedatrial-to-ventricular blood flow. The most common form of PSVT is AVnodal reentrant tachycardia (AVNRT), a disorder characterized by thedevelopment of conducting tissue proximal to the AV node. This tissueforms a closed loop known as a reentry circuit, which enables actionpotentials to be propagated circularly throughout the heart rather thanin a linear fashion. As a result, patients experience rapid palpitationsand severely elevated heart rates. Episodes of tachycardia are oftenaccompanied by a drop in blood pressure, which can induce dizziness orfainting. It is estimated that PSVT affects greater than 1.7 milliontreatable patients in the United States, and over 89,000 new cases arereported annually. Strikingly, many of these patients do not exhibitother signs of cardiovascular disease. Episodes of PSVT can be inducedby various factors, including physical and psychological stress,infection, anemia, menstruation, and pregnancy (Lee, et al., Curr.Probl. Cardiol, 2008, 33:467-546).

Current Modes of Treatment

There are currently several therapeutic modalities available to PSVTpatients. However, these platforms generally suffer from severaldeficiencies, chief among them being invasiveness or inefficiency.Patients can frequent the emergency room for immediate interventionduring an episode, but this strategy provides only temporary relief.Such patients may continue to experience episodes of tachycardiathroughout their lifetimes. Patients who suffer from chronic episodes ofPSVT can have the nodal fibers that propagate anomalous actionpotentials ablated in order to permanently disrupt the mechanism thatunderlies the irregular cardiomyocyte contractions. This proceduretypically requires that a catheter tube be inserted into the patient'sthroat in order to access the heart, where a low-voltage pulse ofelectricity is delivered to the aberrant signaling tissue. This processis highly invasive, and patients are often fearful of undergoing thisform of treatment.

Alternatively, patients who suffer from chronic PSVT can take oralmedication to help attenuate the severity or reduce the frequency ofarrhythmia episodes. Calcium channel blockers represent a class ofcompounds that is functionally well-suited to ameliorate the symptoms oftachycardia, as these compounds are capable of reducing the influx ofextracellular calcium into cardiomyocytes that ultimately leads tomuscle contraction. Prevalent examples of calcium channel antagonistsinclude verapamil and diltiazem, both of which are potent inhibitors ofcalcium influx and are widely used to treat PSVT. However, despite thewidespread use of these therapeutics, patients who take thesemedications may continue to experience episodes of tachycardia.

There currently is no commercially available therapeutic product thatcan be self-administered during an episode of PSVT in order to alleviatethe symptoms during the episode. While calcium channel blockers providea validated strategy for terminating such episodes, the development ofsuch a product is a challenge due to the precise pharmacokinetic profilenecessary to rapidly alleviate the symptoms without potentiating offtarget-mediated toxicity. A desirable therapeutic must have the capacityfor rapid infusion into the bloodstream of a patient in atherapeutically effective quantity and thus promptly terminate anepisode of PSVT. The drug must be subsequently metabolized andinactivated in rapid fashion for a normal resting heart rate to beestablished. Current calcium channel blocker formulations are designedfor oral administration. The passage of these compounds into thegastrointestinal tract and the ensuing metabolism that occurs hindersthe rapid entry of these drugs into the bloodstream and renders theideal pharmacokinetic profile inaccessible. Instead, these drugs arereleased on a slower time scale via absorption through the intestinalepithelium, which delays their access to faulty cardiac muscle tissue.

The invention disclosed herein provides an innovative strategy fortreating cardiac arrhythmias, such as PSVT. The instant inventionincludes a novel formulation of a calcium channel blocker that enablesthe rapid delivery of the active compound into the bloodstream so as toreach maximum concentrations in plasma of PSVT patients within minutesof administration. This facilitates the rapid termination of PSVTepisodes. The formulation provides an additional benefit in that theactive calcium channel blocker is subsequently metabolized andinactivated rapidly after reaching maximal plasma concentrations. Thispharmacokinetic profile is ideal for a drug that can treat PSVTimmediately during an episode. The formulation of the present inventionthus represents a new therapeutic paradigm for targeting faulty cardiacsignaling in a precise and rapid fashion.

SUMMARY OF THE INVENTION

The present invention relates to the use of an aqueous solution thatcontains a pharmaceutically effective amount of a salt of a calciumchannel antagonist for use in treating stable angina, migraine, andcardiac arrhythmia, such as PSVT. The salts of the instant invention areformulated for nasal administration, which represents an administrationroute that has not previously been exploited for treating PSVT. One ofthe challenges associated with nasal administration is the volumetriclimit imposed by the nasal cavity. Administration of nasal sprays istypically limited to approximately 150 to 200 μL, beyond which point theliquid solution begins to enter the throat. This, in turn, imposes alimit on the quantity of a pharmaceutically active agent that can bedelivered to the epithelial lining of the nasal cavity. The salts of theinstant invention exhibit a surprisingly high solubility in aqueoussolution, which enables the development of concentrated liquid solutionsthat can deliver therapeutically effective quantities of the activeagent to the nasal epithelium. Nasal administration of the active agentis beneficial for achieving an ideal pharmacokinetic profile, as theability of the therapeutic compound to traverse the nasal mucosa andrapidly enter the bloodstream renders the drug capable of quicklytargeting faulty signaling in muscle tissue. The novel formulationsdescribed herein represent a new therapeutic regimen for alleviating thesymptoms of stable angina, migraine, and cardiac arrhythmia, such asPSVT, during an episode.

Embodiments of the invention include an aqueous composition formulatedfor nasal administration containing a pharmaceutically acceptable saltor free base of a compound selected from the group consisting of acompound of the formula

verapamil(2-(3,4-dimethoxyphenyl)-5-[2-(3,4-dimethoxyphenyl)ethyl-methylamino]-2-propan-2-ylpentanenitrile),represented the formula

gallopamil(5-[2-(3,4-dimethoxyphenyl)ethyl-methylamino]-2-propan-2-yl-2-(3,4,5-trimethoxyphenyl)pentanenitrile),represented by the formula

and devapamil(2-(3,4-Dimethoxyphenyl)-2-isopropyl-5-((m-methoxyphenethyl)methylamino)valcronitrile),represented by the formula

or a racemate or enantiomer thereof, wherein the compound is dissolvedin the aqueous composition at a concentration of between 150 mg/mL and600 mg/mL.

In certain embodiments, the compound that is dissolved in the aqueouscomposition is compound I. In preferred embodiments, the compound thatis dissolved in the aqueous composition is the S-enantiomer of compoundI.

Embodiments of the present invention include an aqueous compositionformulated for nasal administration containing a pharmaceuticallyacceptable salt or free base of a compound selected from the groupconsisting of

or a racemate or enantiomer thereof, wherein the compound is dissolvedin the aqueous composition at a concentration of between 150 mg/mL and600 mg/mL.

Embodiments of the present invention also include an aqueous compositionformulated for nasal administration containing a pharmaceuticallyacceptable salt or free base of a compound selected from the groupconsisting of

or a racemate or enantiomer thereof, wherein the compound is dissolvedin the aqueous composition at a concentration of between 150 mg/mL and600 mg/mL.

In particular embodiments, the concentration of the compound that isdissolved in the aqueous solution is approximately 350 mg/mL. Inalternative embodiments, the concentration of the compound that isdissolved in the aqueous solution is approximately 450 mg/mL. In certaincases, the aqueous composition of the instant invention includes from40% to 85% (w/v) water. In additional embodiments of the invention, theaqueous composition has a pH of 4.5±1.5.

Embodiments of the present invention include the aqueous composition ofany of the above embodiments, wherein the aqueous composition contains acompound described herein, e.g., compound I, verapamil, gallopamil, ordevapamil and between 0.5 and 1.5 molar equivalents of acetic acidrelative to the compound. Alternative embodiments of the presentinvention include the aqueous composition of any of the aboveembodiments, wherein the aqueous composition contains a compounddescribed herein, e.g., compound I, verapamil, gallopamil, or devapamiland between 0.5 and 1.5 molar equivalents of methanesulfonic acidrelative to the compound.

In certain cases, the invention includes the composition of any of theabove embodiments, wherein the composition contains a chelating agent.In certain embodiments, the chelating agent is an aminopolycarboxylicacid.

Additional embodiments of the invention include the composition of anyof the above embodiments, wherein the aqueous composition containsethylenediaminetetracetic acid (EDTA).

In other embodiments of the instant invention, the composition of any ofthe above embodiments includes a pH adjusting agent selected from thegroup consisting of sulfuric acid and methanesulfonic acid. In preferredembodiments, the pH adjusting agent is sulfuric acid.

Additional embodiments of the invention include the composition of anyof the above embodiments, wherein the composition exhibits a viscosityof between 10 mPa*s and 70 mPa*s.

Additional aspects of the invention include the composition of any oneof the above embodiments, wherein the composition includes apharmaceutically acceptable excipient. In particular embodiments of theinvention, the excipient is selected from the group consisting ofpolysorbate and propylene glycol.

Embodiments of the invention also include the composition of any of theabove embodiments, wherein the aqueous solution containing the salt of acompound described herein, e.g., compound I, verapamil, gallopamil, ordevapamil remains homogenous at room temperature. In certain cases, theaqueous solution containing the salt of a compound described herein,e.g., compound I, verapamil, gallopamil, or devapamil remainshomogeneous at 10° C. for 4 days. In other cases, the aqueous solutioncontaining the salt of compound I remains homogeneous at 2-5° C. for 7days.

The present invention also includes a nasal delivery system containing acomposition of any one of the above embodiments in a unit dosage formthat contains no more than four single pump spray dosages. Inalternative embodiments, the nasal delivery system contains thecomposition of any of the above embodiments in a unit dosage form thatcontains no more than two single pump spray dosages.

In other embodiments of the invention, the unit dosage form of the nasaldelivery system is configured for administration of no more than 200microliters of the composition to each nostril of a patient. Inalternative forms of the invention, the unit dosage form of the nasaldelivery system is configured for administration of no more than 150microliters of the composition to each nostril of a patient.

Embodiments of the present invention additionally include a compositionthat contains the acetate salt of a compound described herein, e.g.,compound I, verapamil, gallopamil, or devapamil. In alternativeembodiments, the invention includes a composition that contains themethanesulfonate salt of a compound described herein, e.g., compound I,verapamil, gallopamil, or devapamil.

Alternative embodiments of the invention include a method for enhancingpermeability through the nasal epithelium of an aqueous solution thatcontains the acetate salt or methanesulfonate salt of a compounddescribed herein, e.g., compound I, verapamil, gallopamil, or devapamilformulated as a nasal spray solution, wherein the concentration of thesalt of a compound described herein, e.g., compound I, verapamil,gallopamil, or devapamil is between 150 and 600 mg/mL and the pH of thesolution is 4.5±1.5, the method including about 5 mM EDTA in the nasalspray solution.

Additional embodiments of the invention include a method of treating adisease selected from the group consisting of cardiac arrhythmia, stableangina, and migraine, the method including nasally administering to apatient in need thereof an aqueous composition that contains apharmaceutically acceptable salt of a compound described herein, e.g.,compound I, verapamil, gallopamil, or devapamil, wherein the compound isdissolved in the aqueous composition at a concentration of between 150mg/mL and 600 mg/mL. In certain embodiments, the disease is cardiacarrhythmia. In other embodiments, the disease is stable angina. Inalternative embodiments, the disease is migraine. In particularembodiments, the cardiac arrhythmia is PSVT, atrial fibrillation, orventricular tachycardia.

Embodiments of the invention include the method of any of the aboveembodiments, wherein the compound reaches a therapeutically effectiveconcentration in plasma of the patient within 3 to 5 minutes ofadministration to the patient.

Embodiments of the invention also include the method of any of the aboveembodiments that further includes administering between 150 microlitersand 200 microliters of the aqueous composition to the patient.

Preferred embodiments of the invention include the method of any of theabove embodiments, wherein the patient is a human.

Additional embodiments of the invention include the use of thecomposition of any one of the above embodiments in the manufacture of amedicament for the treatment of a disease selected from the groupconsisting of cardiac arrhythmia, stable angina, and migraine. Incertain embodiments, the disease is cardiac arrhythmia. In otherembodiments, the disease is stable angina. In alternative embodiments,the disease is migraine. In particular embodiments, the cardiacarrhythmia is PSVT, atrial fibrillation, or ventricular tachycardia.

The invention also includes a method of making a solution formulated fornasal administration to a patient, wherein the method includes the stepsof

-   -   a. adding a solution containing a first dissolved acid to the        free base of the compound of any of the above embodiments to        form a mixture;    -   b. adding to the mixture a solution that contains        ethylenediaminetetracetic acid;    -   c. heating and mechanically stirring the resulting mixture until        the compound has fully dispersed within the mixture;    -   d. adjusting the pH of the mixture by adding a solution        containing a second dissolved acid to the mixture; and    -   e. diluting the mixture such that the final concentration of the        compound in solution is at least 300 mg per 1 milliliter.

In certain embodiments of the invention, the first dissolved acid isselected from the group consisting of acetic acid and methanesulfonicacid.

In particular embodiments, the second dissolved acid is selected fromthe group consisting of acetic acid, sulfuric acid, and methanesulfonicacid.

In additional embodiments, the final pH of the solution is between about4.0 and about 5.0. In preferred embodiments, the final pH of thesolution is about 4.5.

Embodiments of the invention also include the above-described method,wherein the solution that contains the salt of a compound describedherein, e.g., compound I, verapamil, gallopamil, or devapamil remainshomogenous at 10° C. for 4 days. In alternative embodiments, thesolution that contains the salt of a compound described herein, e.g.,compound I, verapamil, gallopamil, or devapamil remains homogeneous at2-5° C. for 7 days.

Definitions

The term “tachycardia” as used herein refers to a resting heart ratethat is elevated relative to a normal state.

“Cardiac arrhythmia” as used herein refers to a condition characterizedby abnormal heart rhythms that are irregular, too fast, too slow, orconducted via an abnormal electrical pathway through the heart. Cardiacarrhythmias include atrial fibrillation that is characterized byabnormally fast electrical discharge patterns that cause the atria tocontract very rapidly thereby impairing efficient pumping of the bloodinto the ventricles. Cardiac arrhythmias also include PSVT that ischaracterized by a regular and fast heart rate originating in hearttissue above the ventricles. Cardiac arrhythmias also includeventricular tachycardia that is characterized by a rapid heartbeat thatoriginates in the lower chambers of the heart.

The term “angina” as used herein refers to chest discomfort experienceddue to ischemic heart disease. “Stable angina” is angina that isprincipally caused by arteriosclerosis.

The term “migraine” as used herein is a disease characterized by arecurrent headache that typically affects one side of the head and isoften accompanied by nausea, vomiting, or sensitivity to light.

The term “excipient” is used herein to describe any ingredient otherthan an active compound (e.g., one having Formula I) described herein.Excipients may include, for example: antiadherents, antioxidants,binders, coatings, compression aids, disintegrants, dyes (colors),emollients, emulsifiers, fillers (diluents), film formers or coatings,flavors, fragrances, glidants (flow enhancers), lubricants,preservatives, printing inks, sorbents, suspensing or dispersing agents,sweeteners, or waters of hydration. Exemplary excipients include, butare not limited to: butylated hydroxytoluene (BHT), calcium carbonate,calcium phosphate (dibasic), calcium stearate, croscarmellose,crosslinked polyvinyl pyrrolidone, citric acid, crospovidone, cysteine,ethylcellulose, gelatin, hydroxypropyl cellulose, hydroxypropylmethylcellulose, lactose, magnesium stearate, maltitol, mannitol,methionine, methylcellulose, methyl paraben, microcrystalline cellulose,polyethylene glycol, polyvinyl pyrrolidone, povidone, pregelatinizedstarch, propyl paraben, retinyl palmitate, shellac, silicon dioxide,sodium carboxymethyl cellulose, sodium citrate, sodium starch glycolate,sorbitol, starch (corn), stearic acid, stearic acid, sucrose, talc,titanium dioxide, vitamin A, vitamin E, vitamin C, and xylitol.Additional excipients may include, without limitation, polysorbate,propylene glycol, hydroxypropyl β-cyclodextrin, triethylcitrate,benzalkonium chloride, and N-dodecyl-β-D-maltoside.

As used herein, a “chelating agent” is a molecule capable of forming atleast two chemical bonds with a metal cation so as to form a complex.

As used herein, an “aminopolycarboxylic acid” is a molecule thatincludes at least one amine and at least two carboxylic acid functionalgroups. The carboxylic acids of an aminopolycarboxylic acid may bedeprotonated and exist in anionic form as carboxylate groups. Examplesof aminopolycarboxylic acids include, without limitation, iminodiaceticacid (IDA), nitrilotriacetic acid (NTA), pentetic acid (DTPA),ethylenediaminetetracetic acid (EDTA), ethylene glycol tetraacetic acid(EGTA), (1,2-bis(o-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid)(BAPTA), 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid(DOTA), andN—(N-(3-amino-3-carboxypropyl)-3-amino-3-carboxypropyl)azetidine-2-carboxylicacid (nicotianamine), among others.

As used herein, the term “nasal administration” means absorption of acompound or a pharmaceutically acceptable formulation of a compound bycontacting the compound or formulation with the nasal epithelium. Thiscan be achieved by spraying the compound or formulation into the nasalcavity. Desirably the compound is compound I, verapamil, gallopamil, ordevapamil.

As used herein, a “pharmaceutically acceptable salt” or“pharmaceutically acceptable acid addition salt” of a basicpharmaceutically active compound is derived from the treatment of thecompound with an organic acid or an inorganic acid. Exemplarypharmaceutically acceptable acid addition salts include those derivedfrom treatment of the compound with acetic acid or methanesulfonic acid.

A “pharmaceutically acceptable carrier” As used herein, refers to avehicle capable of suspending or dissolving the active compound, andhaving the properties of being nontoxic and non-inflammatory in apatient. Moreover, a pharmaceutically acceptable carrier may include apharmaceutically acceptable additive, such as a preservative,antioxidant, fragrance, emulsifier, dye, or excipient known or used inthe field of drug formulation and that does not significantly interferewith the therapeutic effectiveness of the biological activity of theactive agent, and that is non-toxic to the patient.

The term “pharmaceutically acceptable formulation” As used herein,refers to a composition including a pharmaceutically acceptable carrierand an active compound, e.g., the compound of Formula I.

As used herein, the term “therapeutically effective amount” refers to anamount of an active compound that, when administered to a patient,reduces, eliminates, or prevents one or more symptoms of a cardiacarrhythmia (such as PSVT), stable angina, or migraine. Desirably, atherapeutically effective amount of a pharmaceutical formulation is anaqueous solution that contains a compound of the invention (e.g., acompound having Formula I) in a concentration range of about 150 mg/mLto about 600 mg/mL.

These definitions and others stated in The Merck Manual 16a edition 1992(Chapter 25. pp 461-498; Chapter 25, pp 498-507; and Chapter 24, pp413-429) and Goodman and Gilman's “The Pharmacological Basis ofTherapeutics” 11^(th) edition 2006 (Chapter 34, pp 899-908; Chapter 31,pp 823-824 and pp 830-832; and Chapter 32, pp 845-846) are hereinincorporated by reference.

Other features and advantages of the invention will be apparent from thefollowing Detailed Description and the Claims.

DETAILED DESCRIPTION

The present invention was derived from the surprising discovery that apreviously characterized calcium channel blocker could be formulated asan acid addition salt derived from acetic acid or methanesulfonic acidso as to exhibit very high solubility in aqueous solution. The compoundsof the instant invention include methyl3-(2-((4-cyano-4-(3,4-dimethoxyphenyl)-5-methylhexyl)(methyl)amino)ethyl)benzoate,shown below in Formula I.

Additional compounds of the invention include other calcium channelblockers, such as verapamil, gallopamil, devapamil, and the particularcompounds described herein.

Previously known formulations of calcium channel blockers, such asverapamil and diltiazem, do not provide immediate relief from cardiacarrhythmia, stable angina, or migraine. This is due in part to thepharmacokinetic profile of these drugs as formulated. As oraltherapeutics, these compounds enter the body via gastrointestinal tract,where they are subject to acid-mediated or enzyme-catalyzed degradationand inactivation. These compounds slowly enter the bloodstream viaabsorption by the intestinal epithelium. To date, this route ofadministration has hindered the ability of these drugs to rapidlyantagonize voltage-gated calcium channels at the site of deviant cardiacsignaling that underlies cardiac arrhythmia, such as PSVT. As such,these drugs are commonly taken as a chronic preventative treatmentregimen and are not used for the immediate relief of the symptoms of anepisode of these diseases. Moreover, as calcium signaling also modulatesnormal cardiac muscle contractions, the ideal drug for treatment of anepisode of cardiac arrhythmia, such as PSVT, will be absorbed quicklyand subsequently metabolized and deactivated rapidly so as to mitigateoff-target calcium channel inhibition. Indeed, common side effects oforal formulations of verapamil and diltiazem include attenuatedcardiomyocyte contractility and depressed AV node conduction.

Water Soluble Aqueous Salts

Compound I and other calcium channel blockers, such as verapamil,gallopamil, and devapamil, as well as enantiomers and racemates of thesecompounds, may be dissolved in aqueous solution and formulated for nasaladministration. Nasal administration offers an advantage over oraladministration in that the pharmaceutically active agent can rapidlytraverse the nasal epithelium and immediately enter the bloodstream. Inthis way, once a therapeutically effective amount of the active compoundis in the bloodstream, the compound can disrupt aberrant cardiacsignaling in the anomalous cardiac fibers and provide a patient withrelief from an episode of cardiac arrhythmia, stable angina, or migraineonce it has started. After persisting in the blood for a time sufficientto restore proper cardiomyocyte activity, the compound is metabolizedand deactivated in rapid fashion, so as to prevent prolonged cardiacexposure and harmful side effects.

Despite the validated mechanisms of action of compound I, verapamil,gallopamil, and devapamil, nasal administration requires a highconcentration of an active compound due to the volumetric limit imposedby the nasal cavity. Administration of nasal sprays is typically limitedto approximately 150 to 200 μL, beyond which point the liquid solutionbegins to enter the throat. This, in turn, imposes a limit on thequantity of a pharmaceutically active agent that can be delivered to theepithelial lining of the nasal cavity.

In light of the prevalence of aromatic and saturated aliphatic moietiescoupled with the lack of ionic or hydrogen bond-donating functionality,it was not expected that compound I, verapamil, gallopamil, or devapamilwould be readily soluble in aqueous solution. Moreover, given that asolution of one of these compounds must be highly concentrated so as toenable the delivery of a therapeutically effective quantity of the drugwithin the volume limit imposed by the nasal cavity, prior to thepresent invention, it was unknown whether this could be achieved.

Surprisingly, concentrated aqueous solutions of compound I could be madeby treating this compound with particular organic acids in order toproduce acid addition salts. Methanesulfonic acid and acetic acid werecapable of forming a salt solution with compound I with concentrationssufficient for nasal administration. For nasal administration, adesirable aqueous solution of compound I will exhibit a solubility ofbetween approximately 150 mg/mL and 600 mg/mL (e.g., 150+25 mg/mL,175±25 mg/mL, 200±25 mg/mL, 225±25 mg/mL, 250±25 mg/mL, 275±25 mg/mL,300±25 mg/mL, 325±25 mg/mL, 350±25 mg/mL, 375±25 mg/mL, 400±25 mg/mL,425±25 mg/mL, 450±25 mg/mL, 475±25 mg/mL, 500±25 mg/mL, 525±25 mg/mL,550±25 mg/mL, 575±25 mg/mL, or 600±25 mg/mL). These concentrationscorrespond to a percentage of water of between 40% and 85% (w/v).Surprisingly, it was discovered that acetic acid and methanesulfonicacid were indeed capable of individually producing salts of compound Iwith high solubility in aqueous solution. The high solubility of theacetate and mesylate salts of compound I renders these salts uniquelysuited for nasal administration, as the high concentrations of compoundI attainable in these salt forms enable the delivery of atherapeutically effective amount of the compound within the volumelimitation of the nasal cavity. Given the similarity in chemicalstructure between compound I and verapamil, gallopamil, and devapamil,as well as enantiomers and racemates thereof, these compounds areexpected to be similarly soluble under the conditions described herein.

A common method of measuring the effectiveness of a therapeutic agent interminating an episode of a cardiac arrhythmia, such as PSVT, is byanalysis of an electrocardiogram (ECG) recorded from a patientexperiencing such an episode. The pattern of an ECO describes themagnitude and timing of electrical signaling within the cardiac tissue,and patients suffering from an episode of PSVT typically exhibit adeviant ECG profile that is consistent with the aberrant signaling inthe heart. One of the key features of healthy cardiac signaling is atemporal delay between the initiation of atrial and ventricular actionpotentials. A delay between signaling in the atria and ventricles isnecessary for efficient pumping of blood. Signaling in the atria mustproceed first, such that all blood in the atrial chambers is expelledinto the ventricles before the ventricles contract. This delay iscaptured graphically on an ECG as the PR segment, which is the intervalbetween the beginning of a P wave (corresponding to the onset of atrialdepolarization) and the QRS complex (corresponding to the onset ofventricular depolarization). Patients suffering from an episode of PSVTtypically experience a reduced delay due to aberrant cardiac signalingthat causes the cardiomyocyte tissue to contract irregularly (Basta, etal., Cardiol. Clinics, 1997, 587-598). As such, these patients exhibit areduced PR segment when monitored by ECG analysis.

It has been shown that an increase of at least 10% in the PR segment ofan ECG recorded from a patient suffering from a cardiac arrhythmiacorrelates well with a termination of the PSVT episode. For instance, atherapeutic dose of verapamil administered intravenously to patientssuffering from an episode of PSVT has been shown to induce a PRprolongation of at least 10%, which was correlated with an efficacy of85-90% for terminating the PSVT episode (Reiter, et al., Clin.Pharmacol. Ther., 1982, 711-720). It has also been shown thatintravenous administration of tecadenoson is capable of inducing PSVTtermination with an efficacy of approximately 86% (32 out of 37 patientstreated experienced relief from an episode of PSVT). This result wascorrelated with an average PR prolongation of 8.5%. Collectively, thesedata indicate that a therapeutic agent capable of inducing a PRprolongation of at least about 10% would be expected to be effective interminating an episode of PSVT in a patient. Experiments have beenperformed in which solutions of the invention containing the dissolvedacetate salt of compound I were nasally administered to patientssuffering from an episode of PSVT. The solutions that were administeredto patients contained varying concentrations of the acetate salt ofcompound I. During the study, a solution containing a particularconcentration of the acetate salt of compound I was administered to apatient experiencing an episode of PSVT, and the patient was monitoredby electrocardiography throughout the duration of the experiment.Administration of solutions of the acetate salt of compound I containing60 mg or greater of compound I were capable of inducing a median PRprolongation of greater than 10% in patients experiencing a PSVTepisode. The results of these experiments demonstrate that a dosagecontaining 60 mg of compound I contains an amount of compound I that istherapeutically effective in terminating an episode of PSVT. Otherpreferable doses of a compound described herein, such as compound I,verapamil, gallopamil, or devapamil, include doses that range from 15 mgto 140 mg of the active compound (e.g., 15 mg, 20 mg, 25 mg, 30 mg, 35mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85mg, 90 mg, 95 mg, 100 mg. 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130mg, 135 mg, 140 mg, etc.) An aqueous solution containing the acetate ormethanesulfonate salt of a compound described herein, such as compoundI, verapamil, gallopamil, or devapamil, exhibit a particular viscosityrange. In certain embodiments, the viscosity of such a solution canrange from 10 mPa*s to 70 mPa*s (e.g., 10 mPa*s, 15 mPa*s, 20 mPa*s, 25mPa*s, 30 mPa*s, 35 mPa*s, 40 mPa*s, 45 mPa*s, 50 mPa*s, 55 mPa*s, 60mPa*s, 65 mPa*s, or 70 mPa*s). For example, a solution containing a saltof compound I at a concentration of 315 mg/mL exhibited a viscosity ofbetween about 16.515 mPa*s to about 37.505 mPa*s. In another example, asolution containing a salt of compound I at a concentration of 360 mg/mLexhibited a viscosity of between about 25.645 mPa*S to about 63.105mPa*s.

Permeation Enhancer

In order to exhibit an ideal pharmacokinetic profile, a pharmaceuticallyactive compound or pharmaceutically acceptable salt thereof may beformulated with a material capable of enhancing the permeability of theactive agent. In the formulation of the present invention, a compounddescribed herein, such as compound I, verapamil, gallopamil, ordevapamil, will ideally enter the bloodstream rapidly (e.g., within 3 to5 minutes of administration to a patient).

In a preferred embodiment of the present invention, the permeationenhancer of the instant formulation is a chelating agent. Morepreferably, the chelating agent is capable of coordinating divalentcalcium ions (Ca²⁺). It has been shown that the epithelial cells ofmucous membranes are held in close contact by the formation of tightjunctions. The paracellular transport of a pharmaceutically activecompound through the epithelium requires that the compound penetratethese intercellular junctions. Transcellular transport, the alternativeto paracellular transport, requires that a compound penetrate theepithelium by traversing the apical and basolateral membranes, a processfor which many molecules are not well-suited due to their largemolecular volumes. Chelating agents render paracellular transportpossible, however, by binding and sequestering intracellular calcium(Cassidy, et al., J. Cell Biol., 1967, 32:685-698). Calcium is essentialto the biogenesis of tight junctions between epithelial cells, and thereduction of intracellular calcium compromises the integrity of thesejunctions and enables certain molecules to penetrate the intercellularvolume between neighboring cells.

Exemplary chelating agents capable of coordinating calcium ions includeaminopolycarboxylic acids. These include, without limitation,iminodiacetic acid (IDA), nitrilotriacetic acid (NTA), pentetic acid(DTPA), ethylenediaminetetracetic acid (EDTA), ethylene glycoltetraacetic acid (EGTA),(1,2-bis(o-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid) (BAPTA),1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), andN—(N-(3-amino-3-carboxypropyl)-3-amino-3-carboxypropyl)azetidine-2-carboxylicacid (nicotianamine), among others. In a preferred embodiment, thechelating agent is EDTA.

Despite the use of chelating agents such as EDTA to increase thepermeation capacity of drugs through epithelial tissue, it wasnonetheless surprising that the use of EDTA in the instant formulationincreased the permeation of compound I through the nasal epithelium. Thenasal vestibule, which accounts for approximately 3-4% of the surfacearea of the nasal cavity, lacks tight junctions altogether and is thusnot affected by calcium chelating agents. EDTA has been shown tomodulate tight junction formation, but even when junctions arecompromised, the intercellular pores in the nasal epithelium areparticularly small. As such, it has been postulated that the nasalepithelium is not susceptible to permeability modulation by EDTA(Aungst, et al., Pharma. Res., 1998, 5:305-308). Additionally, theability of EDTA to increase permeation of a compound through the nasalepithclium is attenuated as the molecular weight of the compoundincreases (Nakanishi, et al., Chem. Pharm. Bull., 1984, 32:1628-1632).

pH Adjusting Agents

In certain embodiments of the invention, it is desirable to adjust thepH of the aqueous solution including a pharmaceutically acceptable saltof a compound described herein, such as compound I, verapamil,gallopamil, or devapamil. The pH of the formulation can be adjusted bytreating the aqueous solution including a salt of one of these compoundswith a solution including an acidic or a basic reagent. In preferredembodiments, the pH of the formulation is adjusted by titration of theaqueous solution with a solution including an acid. The pH of theformulation is desirably between 3.5 and 5.5, (e.g., 3.5, 3.6, 3.7, 3.8,3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2,5.3, 5.4, or 5.5), and is most desirably 4.5. The pH of the formulationcan be adjusted by adding an aqueous solution containing an acid to theformulation so as to lower the pH to an ideal value. Exemplary acidsthat can be used to titrate an aqueous solution containing a salt of acompound described herein, such as compound I, verapamil, gallopamil, ordevapamil, include, without limitation, acetic acid, sulfuric acid, andmethanesulfonic acid. In preferred embodiments, the acid used to adjustthe pH of the formulation is sulfuric acid or methanesulfonic acid.

Additional Excipients

Formulations of the instant invention may include other agents capableof increasing the permeation, solubility, stability, or efficacy of acompound described herein, such as compound I, verapamil, gallopamil, ordevapamil. Pharmaceutically acceptable excipients may includeantiadherents, antioxidants, binders, coatings, compression aids,disintegrants, dyes (colors), emollients, emulsifiers, fillers(diluents), film formers or coatings, flavors, fragrances, glidants(flow enhancers), lubricants, preservatives, printing inks, sorbents,suspensing or dispersing agents, sweeteners, or waters of hydration.Exemplary excipients include, but are not limited to: butylatedhydroxytoluene (BHT), calcium carbonate, calcium phosphate (dibasic),calcium stearate, croscarmellose, crosslinked polyvinyl pyrrolidone,citric acid, crospovidone, cysteine, ethylcellulose, gelatin,hydroxypropyl cellulose, hydroxypropyl methylcellulose, lactose,magnesium stearate, maltitol, mannitol, methionine, methylcellulose,methyl paraben, microcrystalline cellulose, polyethylene glycol,polyvinyl pyrrolidone, povidone, pregelatinized starch, propyl paraben,retinyl palmitate, shellac, silicon dioxide, sodium carboxymethylcellulose, sodium citrate, sodium starch glycolate, sorbitol, starch(corn), stearic acid, stearic acid, sucrose, talc, titanium dioxide,vitamin A, vitamin E, vitamin C, and xylitol. Additional excipients mayinclude, without limitation, polysorbate, propylene glycol,hydroxypropyl β-cyclodextrin, triethylcitrate, benzalkonium chloride,and N-dodecyl-β-D-maltoside.

The formulation of the present invention may optionally include apharmaceutically acceptable carrier. Examples of a pharmaceuticallyacceptable carrier include, without limitation, a preservative,antioxidant, fragrance, emulsifier, dye, or excipient known or used inthe field of drug formulation and that does not significantly interferewith the therapeutic effectiveness of the biological activity of theactive agent, and that is non-toxic to the patient.

Nasal Delivery System

The present invention additionally provides a nasal delivery system forthe administration of aqueous solutions of salts of a compound describedherein, such as compound I, verapamil, gallopamil, or devapamil, to thenasal cavity of a patient suffering from cardiac arrhythmia, stableangina, or migraine. The nasal delivery system of the invention includesan aqueous solution of the acetate or methanesulfonate salt of acompound described herein, such as compound I, verapamil, gallopamil, ordevapamil, in a unit dosage form. This solution may additionally containother materials, including, without limitation, a permeation enhancer,pharmaceutically acceptable excipient, and/or a pH adjusting agent. Thenasal delivery system includes the unit dosage form as a pump spraydosage. In this way, the nasal delivery system can be used to administeran aqueous solution containing the acetate or methanesulfonate salt of acompound described herein, such as compound I, verapamil, gallopamil, ordevapamil, into the nasal cavity of a patient during an episode ofcardiac arrhythmia, stable angina, or migraine. At the onset of anepisode, a patient can easily self-administer this formulationcontaining one of these active compounds by inserting the applicator ofthe nasal delivery system into the nasal cavity and applying compressilepressure to the pump of the system. This will trigger the release of aspray including the aqueous solution of a salt of the active compoundinto the nasal cavity and onto the nasal epithelium.

The nasal delivery system is analogous to nasal delivery systems thatare commercially available, such as those used to deliver such drugs asImitrex® (sumatriptan), sold by GlaxoSmithKline (Brentford, UK) andZomig® (zolmitriptan), sold by Impax Pharmaceuticals (Hayward, Calif.,USA). These systems include a vial, a piston, a swirl chamber, and anactuator. Upon applying pressure to the actuator, the liquid is forcedthrough the swirl chamber and released as a spray. These nasal deliverysystems often include a pressure point mechanism to ensure that areproducible pressure is applied to the system in order to achieverelease of a consistent volume of spray (Rapoport, et al., Headache,2006, 46:S192-S201). The nasal delivery system of the invention includesa unit dosage form that contains no more than four (e.g., one, two,three, or four single pump spray dosages. In alternative embodiments,the unit dosage form includes no more than two (e.g., one or two) singlepump spray dosages. The unit dosage form can be configured for deliveryof no more than 200 μL (e.g., 200 μL, 190 μL, 180 μL, 170 μL, 160 μL,150 μL, 140 μL, 130 μL, 120 μL, 110 μL, or 100 μL) of the aqueoussolution including a salt of a compound described herein, such ascompound I, verapamil, gallopamil, or devapamil. In alternativeembodiments, the unit dosage form is configured for delivery of no morethan 150 μL (e.g., 150 μL, 140 μL, 130 μL, 120 μL, 110 μL, or 100 μL) ofthe aqueous solution including the acetate or methanesulfonate salt of acompound described herein, such as compound I, verapamil, gallopamil, ordevapamil.

Methods of Formulation

The present invention additionally provides methods of making an aqueoussolution including a salt of a compound described herein, such ascompound I, verapamil, gallopamil, or devapamil. In certain embodimentsof the invention, the free base of one of these compounds is treatedwith a solution including a first dissolved acid. The resulting mixturecontains the acid addition salt including the protonated aminium form ofthe compound and the conjugate base of the first dissolved acid.Examples of the first dissolved acid that are suitable for formation ofthe salt of the active compound include acetic acid and methanesulfonicacid. EDTA may be added to this solution. The first dissolved acid maybe added to the compound so as to form a salt containing the compoundand between 0.5 and 1.5 molar equivalents of the acid. For example, thecompound may be treated with acetic acid in order to form a saltcontaining the compound and between 0.5 and 1.5 molar equivalents ofacetic acid relative to the compound. Alternatively, the compound may betreated with methanesulfonic acid in order to form a salt containing thecompound and between 0.5 and 1.5 equivalents of methanesulfonic acidrelative to the compound. In particular embodiments, the mixturecontaining the salt is heated and mechanically stirred until thecompound has fully dispersed within the mixture. In additionalembodiments, the pH of the mixture is then adjusted by adding a solutionincluding second dissolved acid to this mixture. Examples of the seconddissolved acid useful for adjusting the pH of the formulation includeacetic acid, sulfuric acid, and methanesulfonic acid. In preferredembodiments, the second dissolved acid is sulfuric acid. In particularembodiments, the solution is subsequently diluted such that the finalconcentration of the compound in the mixture is at least 300 mg per 1milliliter (e.g., 300 mg/mL, 310 mg/mL, 320 mg/mL, 330 mg/mL, 340 mg/mL,350 mg/mL, 360 mg/mL, 370 mg/mL, 380 mg/mL, 390 mg/mL, 400 mg/mL, 410mg/mL, 420 mg/mL, 430 mg/mL, 440 mg/mL, 450 mg/mL, 460 mg/mL, 470 mg/mL,480 mg/mL, 490 mg/mL, 500 mg/mL, 510 mg/mL, 520 mg/mL, 530 mg/mL, 540mg/mL, 550 mg/mL, 560 mg/mL, 570 mg/mL, 580 mg/mL, 590 mg/mL, 600 mg/mL,etc).

The acetate and methanesulfonate salts of a compound described herein,such as compound I, verapamil, gallopamil, or devapamil, can exhibitvery high solubility in aqueous solution. An aqueous solution containingone of these salts can remain homogeneous for extended periods of time,even at high concentrations and at reduced temperatures. For example,highly concentrated solutions containing compound I and between 0.5 and1.5 molar equivalents of acetic acid or methanesulfonic acid relative tothe compound remain homogeneous at room temperature with no observableprecipitation. In certain embodiments, these solutions remainhomogeneous at 10° C. for at least 4 days, and in alternativeembodiments these solutions are remain homogeneous at 2-5° C. for atleast 7 days. For example, an aqueous solution containing 300 mg/mL ofcompound I, one molar equivalent of methanesulfonic acid 10 mM sodiumacetate, and 5 mM disodium EDTA, adjusted to a pH of 4.5 withmethanesulfonic acid, remains homogeneous at room temperature and at2-5° C. without any observable precipitation. Moreover, this solutionremains homogeneous even at 0° C. for at least 7 days. Additionally, anaqueous solution containing 400 mg/mL of compound I, one molarequivalent of methanesulfonic acid relative to compound I, 10 mM sodiumacetate, and 5 mM disodium EDTA, adjusted to a pH of 4.5 withmethanesulfonic acid also remains homogeneous at room temperature, 2-5°C. and remains homogeneous at 0° C. for at least 7 days. In anotherexample, a solution containing 350 mg/mL of compound I and one molarequivalent of acetic acid relative to compound I, adjusted to a pH of4.5 with 3.6 M sulfuric acid remains homogeneous at room temperature andalso remains homogeneous at 10° C. for at least 3 days. Additionally, asolution containing over 500 mg/mL of compound I and one molarequivalent of acetic acid relative to compound I, adjusted to a pH of4.5 with 3.6 M sulfuric acid remains homogeneous at room temperature.

In order that this invention be more fully understood, the followingexamples are set forth. These examples are for the purpose ofillustration only and are not to be construed as limiting the scope ofthe invention in any way.

EXAMPLES Example 1: Synthesis methyl3-(2-((4-cyano-4-(3,4-dimethoxyphenyl)-5-methylhexyl)(methyl)amino)ethyl)benzoatePart I: Synthesis of5-Bromo-2-(3,4-dimethoxyphenyl)-2-isopropylpentanenitrile

Method A, Step I:

To a solution of 9.99 g (56.4 mmol) of (3,4-Dimethoxyphenyl)acetonitrilein 141 mL of tetrahydrofuran (THF) at −30° C., was slowly added 56.4 mL(56.4 mmol) of sodium bis(trimethylsilyl)amide (NaHMDS, 1.0 M in THF).The mixture was stirred at −30° C. for 10 minutes and 10.6 mL (113.0mmol) of 2-bromopropane was added. The mixture was heated to reflux for2 hours (h) then left at 22° C. for about 16 h. A saturated aqueoussolution of NH₄Cl was added and the mixture was extracted with ethylacetate. The organic layer was washed with brine, dried (Na₂SO₄),filtered and evaporated. The residue was purified by flashchromatography on silica gel eluting first with hexane and thengradually increasing to 15% ethyl acetate/hexane to give2-(3,4-dimethoxyphenyl)-3-methyl)-3-methylbutanenitrile as an oil.

Method A, Step 2:

To a solution of 11.21 g (51.1 mmol) of2-(3,4-dimethoxyphenyl)-3-methylbutanenitrile in 126 mL oftetrahydrofuran (THF) at −30° C., was slowly added 46.0 mL (46.0 mmol)of sodium bis(trimethylsilyl)amide (NaHMDS, 1.0 M in THF). The mixturewas stirred at −30° C. for 10 minutes and 9.40 mL (256 mmol) of1,3-dibromopropane was added dropwise. The mixture was warmed to 22° C.and stirred for about 16 h. A saturated aqueous solution of NH₄Cl wasthen added and the mixture was extracted with ethyl acetate. The organiclayer was washed with brine, dried (Na₂SO₄), filtered and evaporated.The residue was purified by flash chromatography on silica gel elutingfirst with hexane and then gradually increasing to 15% ethylacetate/hexane to give5-bromo-2-(3,4-dimethoxyphenyl)-2-isopropylpentanenitrile as an oil.

Part II: Synthesis of methyl 3-(2-(methylamino)ethyl)benzoate

To a solution of 5.71 g (24.9 mmol) of methyl 3-bromomethylbenzoate in36 mL of methanol was added 2.11 g (32.4 mmol) of potassium cyanide. Themixture was refluxed for about 16 h, cooled to 22° C. and filtered. Thefiltrate was evaporated and the residue was purified by flashchromatography on silica gel, eluting first with hexane and thengradually increasing to 15% ethyl acetate/hexane to give methyl3-(cyanomethyl)benzoate.

To a solution of 1.31 g (7.48 mmol) of methyl 3-(cyanomethyl)benzoate in31 mL of THF stirred at −10° C. was slowly added 710 mg (18.7 mmol) ofsodium borohydride followed by 1.44 mL (18.7 mmol) of trifluoroaceticacid. The mixture was warmed to 22° C. and stirred for about 16 h. About100 mL of water was carefully added to the mixture (gas evolution). Themixture was extracted with ethyl acetate (5×50 mL). The organic phasewas washed with brine, dried (Na₂SO₄), filtered and evaporated to givemethyl 3-(2-aminoethyl)benzoate which was used in the next step withoutpurification.

Method B:

To 5.12 g (28.6 mmol) of methyl 3-(2-aminoethyl)benzoate in 71 mLtetrahydrofuran (THF) was added 7.48 g (34.3 mmol) of BOC₂O. The mixturewas stirred for about 16 h at 22° C. and 100 mL of water was added. Themixture was extracted with ethyl acetate (2×100 mL) and the organicphase was washed with brine, dried (Na₂SO₄) and evaporated. The residuewas purified by flash chromatography on silica gel, eluting first withhexane and then gradually increasing to 20% ethyl acetate/hexane to givemethyl 3-(2-(tert-butoxycarbonylamino)ethyl)benzoate which was furtherconverted to III by Method C (described below).

Method C, Step 1:

To a solution of methyl 3-(2-(tert-butoxycarbonylamino)ethyl)benzoate indry THF under a nitrogen atmosphere was added dropwise NaHMDS (1.0 M inTHF) at 0° C. After stirring for 10 min, dimethyl sulfate was added andthe reaction was warmed to 22° C. and stirred for about 16 h. Thereaction was quenched by adding 25 mL of saturated NaHCO₃ and themixture was extracted with DCM (2×25 mL). The combined organic extractswere dried (Na₂SO₄) and evaporated and the residue was purified by flashchromatography on silica gel, eluting first with hexane and thengradually increasing to 10/o ethyl acetate/hexane to give methyl3-(2-(tert-butoxycarbonyl(methyl)amino) ethyl)benzoate.

Method C, Step 2:

To a solution of methyl 3-(2-(tert-butoxycarbonyl(methyl)amino)ethyl)benzoate in DCM at 0° C. was added trifluoroacetic acid (TFA). Thereaction was warmed to 22° C., stirred for 3 h and the solvents werethen evaporated. The residue was partitioned between 100 mL of ethylacetate and 100 mL of 1 N NaOH which had been saturated with NaCl. Theaqueous layer was back-extracted with ethyl acetate (6×50 mL) and thecombined organics were dried (Na₂SO₄) and evaporated to give 2c as acolorless oil.

Part III: Reaction of Compound II with Compound III Produced Compound I

Analysis of the product by mass spectrometry revealed a peak with amass-to-charge ratio (m/z) of 453, corresponding to the M+H molecularion of compound I.

Example 2: Concentrated Solution of Acetate Salt of Compound I

A concentrated aqueous solution of the acetate salt of compound I isformed according to the following protocol:

An aqueous solution of 7.5 M sulfuric acid is first made by dilutingconcentrated sulfuric acid in water and manually mixing in a sealedbottle, periodically venting the pressure by releasing the bottle cap.Separately, 175±1.0 g of compound I is dispensed from a pre-heatedcontainer into a glass bottle and maintained at a temperature of 50±2°C. in a water bath. Next, 96.7±0.2 mL of a 4.0 M acetic acid solution isadded to compound I, followed by 83.3 mL±0.2 mL of a 31.8 mM solution ofEDTA. The mixture containing the (−) enantiomer (S-enantiomer) ofcompound I is maintained at 50±2° C. and stirred using a magnetic stirbar during both additions. Heating and stirring is continued until thecompound appears to be fully dispersed throughout the mixture.

Upon complete dispersion of compound I, the solution of 7.5 M sulfuricacid is added drop-wise to the compound I mixture until a pH of 5.0±0.1is reached. At this point, heating is discontinued and the mixturecontinues to stir. The mixture is then allowed to cool to within 2° C.of ambient temperature. A solution of 0.9 M sulfuric acid is then addeddrop-wise to the mixture until a pH of 4.5±0.1 is reached. The mixturecontaining compound I is then diluted to 90% of the final target volumeby the addition of water to the mixture, and the pH is monitored afterthis dilution. If necessary, the pH is lowered back to 4.5±0.1 bydrop-wise addition of 0.9 M sulfuric acid. The mixture is then dilutedto the final target volume by the addition of water.

This protocol readily can be adapted to provide a concentrated solutionof the methanesulfonate salt of compound I.

Example 3: Nasal Administration of Compound I

A patient experiencing an episode of PSVT can use a nasal deliverysystem containing the acetate or methanesulfonate salt of compound I inorder to nasally self-administer a therapeutically effective amount ofcompound I and alleviate the symptoms of this episode. At the onset ofan episode of PSVT, a patient can hold the nasal delivery system up tothe nose, such that the applicator of the system is inserted into thenasal cavity. The nasal delivery system is typically held between thesecond and third fingers, and the patient's thumb is placed on theactuator. This process is similar to the use of commercially availablenasal delivery systems such as those used to deliver such drugs asImitrex® (sumatriptan), sold by GlaxoSmithKline (Brentford, UK) andZomig® (zolmitriptan), sold by Impax Pharmaceuticals (Hayward, Calif.,USA). The patient can then apply pressure to the actuator, which forcesthe liquid solution containing the dissolved acetate or methanesulfonatesalt of compound I through a swirl chamber, causing the solution to bereleased from the tip of the applicator as a spray. The solution may beadministered as one, two, three, or four single pump spray dosages inorder to deliver 60 mg or more of compound I to the nasal epithelium.

The spray administered as described delivers the solution containing theacetate or methanesulfonate salt of compound I to the nasal epithelium,allowing compound I to be penetrate the epithelium and rapidly enter thebloodstream. The acetate or methanesulfonate salt of compound Iadministered in this way reaches a maximum concentration in plasmawithin 3 to 5 minutes after administration to the patient, and minimalconcentrations of the compound in plasma are observed within 50 to 60minutes of administration. In this manner, the patient experiencesrelief from an episode of PSVT very soon after administration, andbecause of the ideal pharmacokinetic profile of compound I, the drugdoes not persist in the bloodstream long enough to induce adverse sideeffects.

Other Embodiments

While the invention has been described in connection with specificembodiments thereof, it will be understood that it is capable of furthermodifications and this application is intended to cover any variations,uses, or adaptations of the invention following, in general, theprinciples of the invention and including such departures from thepresent disclosure come within known or customary practice within theart to which the invention pertains and may be applied to the essentialfeatures hereinbefore set forth.

All references, patents, patent application publications, and patentapplications cited herein are hereby incorporated by reference to thesame extent as if each of these references, patents, patent applicationpublications, and patent applications were separately incorporated byreference herein.

What is claimed is:
 1. An aqueous composition formulated for nasaladministration comprising a pharmaceutically acceptable salt or freebase of a compound selected from the group consisting of

verapamil, gallopamil, and devapamil, or a racemate or enantiomerthereof, wherein the compound is dissolved in the aqueous composition ata concentration of between 150 mg/mL and 600 mg/mL.
 2. The aqueouscomposition of claim 1, wherein the compound is compound I.
 3. Theaqueous composition of claim 2, wherein the compound is the S-enantiomerof compound I.
 4. The aqueous composition of any one of claims 1-3,wherein the concentration is approximately 350 mg/mL.
 5. The aqueouscomposition of any one of claims 1-3, wherein the concentration isapproximately 450 mg/mL.
 6. The aqueous composition of any one of claims1-3, wherein the aqueous composition comprises from 40% to 85% (w/v)water.
 7. The aqueous composition of any one of claims 1-3, wherein theaqueous composition has a pH of 4.5±1.5.
 8. The composition of any oneof claims 1-7, wherein the aqueous composition comprises a compoundselected from the group consisting of compound I, verapamil, gallopamil,and devapamil and between 0.5 and 1.5 molar equivalents of acetic acidrelative to the compound.
 9. The composition of any one of claims 1-7,wherein the aqueous composition comprises a compound selected from thegroup consisting of compound I, verapamil, gallopamil, and devapamil andbetween 0.5 and 1.5 molar equivalents of methanesulfonic acid relativeto the compound.
 10. The aqueous composition of any one of claims 1-9,wherein the composition further comprises a chelating agent.
 11. Thecomposition of claim 10, wherein the chelating agent is anaminopolycarboxylic acid.
 12. The composition of claim any one of claims1-11, wherein the aqueous composition further comprises EDTA.
 13. Thecomposition of any one of claims 1-12, wherein the composition furthercomprises a pH adjusting agent selected from the group consisting ofsulfuric acid and methanesulfonic acid.
 14. The composition of claim 13,wherein the pH adjusting agent is sulfuric acid.
 15. The composition ofany one of claims 1-14, wherein the composition exhibits a viscosity ofbetween 10 mPa*s and 70 mPa*s.
 16. The composition of any one of claims1-15, wherein the composition further comprises a pharmaceuticallyacceptable excipient.
 17. The composition of claim 16, wherein theexcipient is polysorbate or propylene glycol.
 18. The composition of anyone of claims 1-17, wherein the aqueous solution comprising the salt ofa compound selected from the group consisting of compound I, verapamil,gallopamil, and devapamil remains homogeneous at room temperature. 19.The composition of any one of claims 1-17, wherein the aqueous solutioncomprising the salt of a compound selected from the group consisting ofcompound I, verapamil, gallopamil, and devapamil remains homogeneous at0.10° C. for 4 days.
 20. The composition of any one of claims 1-17,wherein the aqueous solution comprising the salt of a compound selectedfrom the group consisting of compound I, verapamil, gallopamil, anddevapamil remains homogeneous at 2-5° C. for 7 days.
 21. A nasaldelivery system comprising a composition of any one of claims 1-20 in aunit dosage form comprising no more than four single pump spray dosages.22. A nasal delivery system comprising a composition or any one ofclaims 1-20 in a unit dosage form comprising no more than two singlepump spray dosages.
 23. The nasal delivery system of claim 21 or 22,wherein the unit dosage form is configured for administration of no morethan 200 microliters of the composition to each nostril of a patient.24. The nasal delivery system of claim 21 or 22, wherein the unit dosageform is configured for administration of no more than 150 microliters ofthe composition to each nostril of a patient.
 25. A compositioncomprising the acetate salt of a compound selected from the groupconsisting of compound I, verapamil, gallopamil, and devapamil.
 26. Acomposition comprising the methanesulfonate salt of a compound selectedfrom the group consisting of compound I, verapamil, gallopamil, anddevapamil.
 27. A method of treating a disease selected from the groupconsisting of cardiac arrhythmia, stable angina, and migraine, saidmethod comprising nasally administering to a patient in need thereof anaqueous composition comprising a pharmaceutically acceptable salt of acompound selected from the group consisting of compound I, verapamil,gallopamil, and devapamil, wherein the compound is dissolved in theaqueous composition at a concentration of between 150 mg/mL and 600mg/mL.
 28. The method of claim 27, wherein said disease is cardiacarrhythmia.
 29. The method of claim 27, wherein said disease is stableangina.
 30. The method of claim 27, wherein said disease is migraine.31. The method of claim 28, wherein said cardiac arrhythmia is PSVT,atrial fibrillation, or ventricular tachycardia.
 32. The method of anyone or claims 27-31, wherein the compound reaches a therapeuticallyeffective concentration in plasma of the patient within 3 to 5 minutesof administration to the patient.
 33. The method of any one of claims27-32, the method comprising administering between 150 microliters and200 microliters of the aqueous composition to the patient.
 34. Themethod of any one of claims 27-33, wherein the patient is a human. 35.Use of the composition of any one of claims 1-20 in the manufacture of amedicament for the treatment of a disease selected from the groupconsisting of cardiac arrhythmia, stable angina, and migraine.
 36. Theuse according to claim 35, wherein said disease is cardiac arrhythmia.37. The use according to claim 35, wherein said disease is stableangina.
 38. The use according to claim 35, wherein said disease ismigraine.
 39. The use according to claim 36, wherein said cardiacarrhythmia is PSVT, atrial fibrillation, or ventricular tachycardia. 40.A method of making a solution formulated for nasal administration to apatient, the method comprising the steps of a. adding a solutioncomprising a first dissolved acid to the free base of a compound ofclaim 1 to form a mixture; b. adding to the mixture a solutioncomprising ethylenediaminetetracetic acid; c. heating and mechanicallystirring the resulting mixture until the compound has fully dispersedwithin the mixture; d. adjusting the pH of the mixture by adding asolution comprising a second dissolved acid to the mixture; and e.diluting the mixture such that the final concentration of the compoundin solution is at least 300 mg per 1 milliliter.
 41. The method of claim40, wherein the first dissolved acid is selected from the groupconsisting of acetic acid and methanesulfonic acid.
 42. The method ofclaim 40, wherein the second dissolved acid is selected from the groupconsisting of acetic acid, sulfuric acid, and methanesulfonic acid. 43.The method of claim 40, wherein the final pH of the solution is betweenabout 4.0 and about 5.0.
 44. The method of claim 43, wherein the finalpH of the solution is about 4.5.
 45. The method of claim 40, wherein thesolution comprising the salt of the compound remains homogeneous at 10°C. for 4 days.
 46. The method of claim 40, wherein the solutioncomprising the salt of the compound remains homogeneous at 2-5° C. for 7days.